The trinuclear BBR3464 ([{trans-PtCl(NH(3))(2)}(2)µ-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](4+)) belongs to the polynuclear class of platinum-based anticancer agents. DNA adducts of this complex differ significantly in structure and type from those of clinically used mononuclear platinum complexes, especially, long-range (Pt, Pt) intrastrand and interstrand cross-links are formed in both 5'-5' and 3'-3' orientations. We show employing short oligonucleotide duplexes containing single, site-specific cross-links of BBR3464 and gel electrophoresis that in contrast to major DNA adducts of clinically used platinum complexes, under physiological conditions the coordination bonds between platinum and N7 of G residues involved in the cross-links of BBR3464 can be cleaved. This cleavage may lead to the linkage isomerization reactions between this metallodrug and double-helical DNA. Differential scanning calorimetry of duplexes containing single, site-specific cross-links of BBR3464 reveals that one of the driving forces that leads to the lability of DNA cross-links of this metallodrug is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross-links originally formed in one strand of DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule.

Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czech Republic

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Hurley LH. DNA and its associated processes as targets for cancer therapy. Nature Rev. Cancer. 2002;2:188–200. PubMed

Cusumano M, DiPietro ML, Giannetto A, Messina MA, Romano F. Catalysis and inhibition of ligand substitution in palladium(II) square-planar complexes: Effects of DNA. J. Am. Chem. Soc. 2001;123:1914–1919. PubMed

Davies MS, Berners-Price SJ, Cox JW, Farrell N. The nature of the DNA template (single- versus double-stranded) affects the rate of aquation of a dinuclear Pt anticancer drug. Chem. Commun. 2003:122–123. PubMed

Comess KM, Costello CE, Lippard SJ. Identification and characterization of a novel linkage isomerization in the reaction of trans- diamminedichloroplatinum(II) with 5′-d (TCTACGCGTTCT) Biochemistry. 1990;29:2102–2110. PubMed

Perez C, Leng M, Malinge JM. Rearrangement of interstrand cross-links into intrastrand cross-links in cis-diamminedichloroplatinum(II)-modified DNA. Nucleic Acids Res. 1997;25:896–903. PubMed PMC

Giraud-Panis M-J, Leng M. Transplatin-modified oligonucleotides as modulators of gene expression. Pharmacol. Therapeutics. 2000;85:175–181. PubMed

Chvalova K, Brabec V, Kasparkova J. Mechanism of the formation of DNA-protein cross-links by antitumor cisplatin. Nucleic Acids Res. 2007;35:1812–1821. PubMed PMC

Kane SA, Lippard SJ. Photoreactivity of platinum(II) in cisplatin-modified DNA affords specific cross-links to HMG domain proteins. Biochemistry. 1996;35:2180–2188. PubMed

Farrell N. Polynuclear platinum drugs. In: Sigel A, Sigel H, editors. Metal Ions in Biological Systems. Vol. 42. New York, Basel: Marcel Dekker Inc.; 2004. pp. 251–296. PubMed

Farrell N, Kelland LR, Roberts JD, Van Beusichem M. Activation of the trans geometry in platinum antitumor complexes: a survey of the cytotoxicity of trans complexes containing planar ligands in murine-L1210 and human tumor panels and studies on their mechanism of action. Cancer Res. 1992;52:5065–5072. PubMed

Jamieson ER, Lippard SJ. Structure, recognition, and processing of cisplatin-DNA adducts. Chem. Rev. 1999;99:2467–2498. PubMed

Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nature Rev. Drug Discov. 2005;4:307–320. PubMed

Davies MS, Thomas DS, Hegmans A, Berners-Price SJ, Farrell N. Kinetic and equilibria studies of the aquation of the trinuclear platinum phase II anticancer agent [{trans-PtCl(NH3)2}2{µ-trans-Pt(NH3)2(NH2(CH2)6NH2)2}]4+ (BBR3464) Inorg. Chem. 2002;41:1101–1109. PubMed

McGregor TD, Hegmans A, Kasparkova J, Neplechova K, Novakova O, Penazova H, Vrana O, Brabec V, Farrell N. A comparison of DNA binding profiles of dinuclear platinum compounds with polyamine linkers and the trinuclear platinum phase II clinical agent BBR3464. J. Biol. Inorg. Chem. 2002;7:397–404. PubMed

Brabec V, Kasparkova J, Vrana O, Novakova O, Cox JW, Qu Y, Farrell N. DNA modifications by a novel bifunctional trinuclear platinum Phase I anticancer agent. Biochemistry. 1999;38:6781–6790. PubMed

Hegmans A, Berners-Price SJ, Davies MS, Thomas D, Humphreys A, Farrell N. Long range 1,4 and 1,6-interstrand cross-links formed by a trinuclear platinum complex. Minor groove pre-association affects kinetics and mechanism of cross-link formation as well as adduct structure. J. Am. Chem. Soc. 2004;126:2166–2180. PubMed

Kasparkova J, Zehnulova J, Farrell N, Brabec V. DNA interstrand cross-links of the novel antitumor trinuclear platinum complex BBR3464. Conformation, recognition by high mobility group domain proteins, and nucleotide excision repair. J. Biol. Chem. 2002;277:48076–48086. PubMed

Zehnulova J, Kasparkova J, Farrell N, Brabec V. Conformation, recognition by high mobility group domain proteins, and nucleotide excision repair of DNA intrastrand cross-links of novel antitumor trinuclear platinum complex BBR3464. J. Biol. Chem. 2001;276:22191–22199. PubMed

Ruhayel RA, Moniodis JJ, Yang X, Kasparkova J, Brabec V, Berners-Price SJ, Farrell NP. Factors affecting DNA-DNA interstrand cross-links in the antiparallel 3′-3′ sense: A comparison with the 5′-5′ directional isomer. Chem. Eur. J. 2009;15:9365–9374. PubMed PMC

Cox JW, Berners-Price S, Davies MS, Qu Y, Farrell N. Kinetic analysis of the stepwise formation of a long-range DNA interstrand cross-link by a dinuclear platinum antitumor complex: Evidence for aquated intermediates and formation of both kinetically and thermodynamically controlled conformers. J. Am. Chem. Soc. 2001;123:1316–1326. PubMed

Brabec V, Reedijk J, Leng M. Sequence-dependent distortions induced in DNA by monofunctional platinum(II) binding. Biochemistry. 1992;31:12397–12402. PubMed

Kasparkova J, Farrell N, Brabec V. Sequence specificity, conformation, and recognition by HMG1 protein of major DNA interstrand cross-links of antitumor dinuclear platinum complexes. J. Biol. Chem. 2000;275:15789–15798. PubMed

Malina J, Hofr C, Maresca L, Natile G, Brabec V. DNA interactions of antitumor cisplatin analogs containing enantiomeric amine ligands. Biophys. J. 2000;78:2008–2021. PubMed PMC

Hofr C, Brabec V. Thermal and thermodynamic properties of duplex DNA containing site-specific interstrand cross-link of antitumor cisplatin or its clinically ineffective trans isomer. J. Biol. Chem. 2001;276:9655–9661. PubMed

Nováková O, Malina J, Kašpárková J, Halámiková A, Bernard V, Intini F, Natile G, Brabec V. Energetics, conformation, and recognition of DNA duplexes modified by methylated analogues of [PtCl(dien)]+ Chem. Eur. J. 2009;15:6211–6221. PubMed

Brabec V, Leng M. DNA interstrand cross-links of trans-diamminedichloroplatinum(II) are preferentially formed between guanine and complementary cytosine residues. Proc. Natl Acad. Sci. USA. 1993;90:5345–5349. PubMed PMC

Boudvillain M, Dalbies R, Aussourd C, Leng M. Intrastrand cross-links are not formed in the reaction between transplatin and native DNA: relation with the clinical inefficiency of transplatin. Nucleic Acids Res. 1995;23:2381–2388. PubMed PMC

Poklar N, Pilch DS, Lippard SJ, Redding EA, Dunham SU, Breslauer KJ. Influence of cisplatin intrastrand crosslinking on the conformation, thermal stability, and energetics of a 20-mer DNA duplex. Proc. Natl Acad. Sci. USA. 1996;93:7606–7611. PubMed PMC

Pilch DS, Dunham SU, Jamieson ER, Lippard SJ, Breslauer KJ. DNA sequence context modulates the impact of a cisplatin 1,2-d(GpG) intrastrand cross-link an the conformational and thermodynamic properties of duplex DNA. J. Mol. Biol. 2000;296:803–812. PubMed

Kasparkova J, Mellish KJ, Qu Y, Brabec V, Farrell N. Site-specific d(GpG) intrastrand cross-links formed by dinuclear platinum complexes. Bending and NMR studies. Biochemistry. 1996;35:16705–16713. PubMed

Marky LA, Breslauer KJ. Calculating thermodynamic data for transitions of any molecularity from equilibrium melting curves. Biopolymers. 1987;26:1601–1620. PubMed